Experiments in this research program are designed to test the hypothesis that in the aged cells, as opposed to mature cells, there is an impairment of hormonal adaptive mechanisms. The adrenergic system has been chosen as the model hormonal system on which the hypothesis will be tested. Our preliminary experiments indicate that in the rat heart there is progressive decrease in beta-adrenergic receptor number and beta-adrenergic receptor coupled adenylate cyclase activity with increasing age. The senescent rat heart also shows impaired beta-adrenoceptor response to thyroid hormone: the many ramifications arising from these preliminary findings are to be explored in the different sections of this research program. What are the mechanisms involved in the causation of the impaired cardiac beta-adrenoceptor-adenylate cyclase coupling during aging? What is the molecular basis for the impaired response of the cardiac beta-adrenoceptors to thyroid hormone in the senescent animals? These are the questions to be addressed in Section I. In Section II the possibility of chronic desensitization as the molecular mechanism causing the decreased cardiac beta-adrenoceptors during aging will be investigated. Section III will attempt to define whether the impaired response of the beta-adrenoceptors to thyroid hormone noted in aged is specific for the cardiac tissue or whether it is more generalized to beta-adrenoceptors in other thyroid hormone responsive tissues. In Section IV cardiac alpha-adrenoceptor alterations during aging and the possible impairment in their adaptive capabilities during senescence will be studied. The study should provide important insights into the molecular mechanisms involved in the alterations occurring in the adrenergic system during the aging process.